Bis-hydrazones



Patented Oct. 13, 1953 I 2,655,540 BIS-HYDRAZONES Heinrich Jensch, FranGermany,

kfurt am Main Hochst, assignor to Farbwerke Hoechst Aktiengesellschaftvormals Meister Lucius und Briining, Frankfurt am Main Hochst, Germany,a company of Germany N 0 Drawing.

Application September 3, 1952,

Serial No. 307,696. In Germany July 24, 1950 6" Claims. (01. 260565) IThe present invention relates to new bis-hydrazones. I have found thathitherto unknown bishydra'zones of aliphatic, vicinal dioxo compoundscan be prepared, which have in one hydrazone group a guanyl radical andin the other a phenyl radical containing one of the followingsubstituents:

The products thus obtained have the following structural formula: 7

CH: W NH NH.N=C R''.( :=N.NH.o t R i v NH:

wherein R stands for a member of the group consisting of and R standsfor a member of thegroupconsisting of hydrogen, methyl, ethyl and allyl.

According to one feature of the invention the specified compounds areobtained by condensing with amino-guanidine a mono-phenyl-hydrazone ofan aliphatic, vicinal dioxo-compound of which the phenyl nucleuscontains one of the specified substituents. As aliphatic, vicinal di-oxocompounds there may be named, for'example, pyroracernic aldehyde,diacetyl, pentane-2.3-dione, hexene (1) -dione(i.5), pentene(1)-dione(4.5) hexane-2.3-dione, and others. u

According to a further feature of the invention the compounds may beobtained by condensing a mono-guanyl-hydrazone of an aliphatic, vicinaldioxo compound with a phenyl hydrazine which contains in the phenylnucleus one of the three specified substituents. i l

According to a stillfurther feature of the invention it is also possibleto condense with amino-guanidine a mono-'phenyl-hydrazone of analiphatic, vicinal di-oxo compound containing in the nucleus a groupwhich can be transformed into one of the specified substituents; and totransform this group into one of the said substituents. 1

' Suitable aliphatic hydrocarbon radicals having 1 to 3 carbonatoms,which may be used according to the present invention, are, for examplemethyl, ethyl, propyl, isopropyl, allyl, vinyl and others. i

The compounds thus obtained are distinguished by their eflicacy inprotozoan infections, i. e. for combating babesia and trypanosomes.Moreover, the compounds possess bactericidal properties.

The following examples serve to illustrate the invention but they arenot intended to limit it thereto:

,is obtained. The solution is then mixed with an excess of dilute nitricacid and the yellowmagma formed on cooling is filtered with suction andwashed with dilute nitric acid. .The dinitrate thus obtained, of thecompound corresponding to the formula given above, is then transformedinto the carbonate by mixing it, whilev stirring,

with sodium carbonate solution. The, carbonate is filtered with suctionand washed with icecold water. After having been dried at ordinarytemperature it constitutes an ochre-yellow powder which, on subsequentlystirring with methanol and acidifying with methanolic hydrochloric'acid,

lowing a solution of ash solution or 2.76

is transformed, with evolution of carbon dioxide, into the hydrochloridewhich, after cooling in ice, is filtered with suction and washed withice-cold methanol. The product is readily soluble in water and moresparingly soluble in dilute hydrochloric acid and in methanol. Whenrecrystallised from methanol and a small quantity of water, it does notmelt up to 300 C. After hav.- ing been recrystallised from water, thedinitrate melts at 276 C. with violent decomposition. The lactate, whichis obtained from the-carbonate in a manner analogous to that ofobtaining the hydrochloride, melts at 253 (L-254: C., withdecomposition.

The starting material, i. e. the pyroracemic aldehyde para guanyl phepylhydrazone hydrochloride, is suitably prepared as follows: Thehydrochloric acid solution of 63 grams of para-amino-benzamidinedihydrochloride (melting at 288 C. with decomposition,para-nitro-compoundby reduction with hydrogen and a nickel catalyst)which solutionhas been diamtized with 21 grams of-sodium nitrite, ismixed with an acetoacetic acid solution obtained by al- 40 gramsofacetoacetic ester to stand for 24 hours in 670 cc. of a caustic potpercent. strength and then acidifying it with 310 cc. of 2 N-hydrochloricacid. 220 cc. of saturated sodium acetate solution are gradually addedto the mixture, while stirring, during which operation a thick,brownish-yellow precipitate is formed with evolution of carbon dioxide;the precipitate is :allowed to stand for several hours, filtered withsuction and washed with N'hydrochloric acid .and acetone. when theproduct has been recrystallised from glacial acetic acid it melts at 255C. with'decomposition. It is readily soluble in vhot water, sparinglysoluble in dilute hydrochloric acid in the cold and soluble in causticsoda solution,

.forming a dark brown-yellow solution.

Example 2 an in; //NH NH.N=CH. ='N;NH.C HIN/ H:

27 grams of pyroracemic aldehyde-metaguanylephenyl-hydrazone with asmall-qrmntitycof dilute nitric acid and then mixed in 200 cc. of waterwith a.solution of 14 grams or aminoguanidine nitra The mixture isheated for 1 hour in a water-bath, while stirring; after cooling, anexcess of dilute nitric acid-is added and the (ii-nitrate correspondingto the above-formula is filtered with suotionand washed with N-nitric Iacid .and acetone. It constitutes a brown-red powder which readilydissolves in hot water; it is moderately soluble in cold water, andafter it has-been recrystallised from water it meltsat 262C.withdecomposition. The carbonate, obtained-therefrom as described inExample 1, constitutes a grey-yellow powder which is dried under reducedpressure and then transformed, in the same manner as the para-compound,into the di-hydrochloride. A brownish-red crystalline 'powder isobtained which, after recrystallisation from methanol and acetone,meltsat 273 C. with decomposition; it is readily soluble in-water,methanol and dilute hydrochloric acid and sparingly soluble in ethanol.

The pyroracemic aldehyde 'meta-guanyl phenyl-hydrazone is prepared in amanner analand obtained from the.

nitrate are acidified solves in water ogous to that of thepara-compound, using metaamino-benzamidine dihydrochloride (see"Berichte der Deutschen Chemischen Gesellschaft, vol. 28, page 486); itis precipitated as the nitrate by mixing the solution 0! itshydrochloride with dilute nitric acid. The nitrate constitutes a lightred to brown powder which, recrystallised trom water, melts at 209C.-210 C. with decomposition.

Erample 3 on. OH: /NH ,NH.N=t:-- =N.NH.C/ EN NH) I HrN "25.5 grams ofdiacetyl-mono-para-guanylphenyl-hydrazone hydrochloride in cc. of waterare mixed with a hot solution of 14 grams of aminoguanidine nitrate in65 ,cc. of water. whereupon the mixture is heated in a water-bath. whilestirring, until dissolutionhas taken place. On coolin a practicallycolorless magma is formed which is stirred with an excess of sodiumcarbonate solution, during which operation it is transformed into thevoluminous carbonate which is centrifuged and washed several times withwater. After drying, the carbonate is mixed with methanol, whilestirring; by acidifying the mixture with methanolic hydrochloric acid,it is transformed into the dihydrochloride which is filtered withsuction and washed with acetone. It constitutes a yellowish powder whichreadily dissolves in water, forming a. reddish-yellow solution. By meansof dilute caustic soda solution the practically colorless crystallinebase of "the above constitution is precipitated from the solution. Afterrecrystallisation from acqueous methanol, the base melts at 240 C. withdecomposition.

The starting material can be obtained according to the method describedin Example 1. in the form of the hydrochloride, by coupling diazotizedpara-amino-benzamidine with methylaceto-acetic acid. The hydrochlorideconstitutes a feebly reddish powder which is sparingly soluble in coldwater and readily soluble in hot water. When recrystallised from water,it melts at 272 'C. with decomposition; the base precipitated withdilute caustic soda solution melts at 199 C.- 200 C. with decomposition.

24.6 grams of diacetyl-mono-meta-gulm lphenyl-hydrazone hydrochlorideare heated in the water-bath together with 50 cc. of water and asolution of 15 grams of amino-guanidine carbonate in about -'70 cc. of 2N-hydrochloric acid until complete dissolution has taken place. Aftercooling. the solution is mixed with concentrated hydrochloric acid andthe salt which has separated is filtered with suction in'the icecoldconditi and washed with ice-cold dilute hydrochloric acid and acetone.The .di-hydrochloride of the above base constitutes an almost colorlessincompact powder which readily dison heating-and forms a yellowsolution. when recrystallised from methanol andacetona it melts at 302C. with decomposition.

decomposition.

Example 5 CzHs CH3 NH 1 NH.N=0 o=N.NH.o

NH2 0 HzN 20.5 grams of pentane 2.3 dione-3-paraguanyl phenylhydrazonehydrochloride are weakly acidified and then heated on the waterbath,while stirring, together with 100 cc. of water and a solution of 9.8grams of aminoguanidine nitrate in 45 cc. of water, until a clearsolution is formed. After cooling in ice, the fine crystallineprecipitate is filtered with suction and stirred with an excess ofsodium carbonate solution. The carbonate is formed during this operationin the form of a precipitate of the nature of a thick oil which, oncooling and rubbing, becomes crystalline. After drying, the carbonate inmethanol is acidified with methanolic hydrochloric acid, during whichoperation a pale yellow magma of the dihydrochloride of the compoundhaving the formula given above, is formed. The compound dissolves inwater and forms a red-yellow solution; when recrystallised from a largequantity of methanol, it melts at 244 C. with decomposition.

The starting material is obtained as described in Example 3, usingethyl-acetoacetic acid. It constitutes a reddish crystalline powderwhich dissolves in hot water and forms a red-yellow solution. The baseis precipitated by means of dilute caustic soda solution. When the basehas been recrystallised from water and a small quantity of methanol, itconstitutes a colorless, fine crystalline powder which, on dryingon thewater-bath, assumes a brown color. It melts at 113 C.-114 C. withdecomposition.

grams of hexene-(l)-dione-(4.5)-4-paraguanylphenyl-hydrazonehydrochloride in 130 cc. of water are weakly acidified with dilutehydrochloric acid and then heated on the waterbath for about hour with asolution of 9.3 grams of amino-guanidine nitrate in cc. of water. Aftercooling, the carbonate is precipitated with potassium carbonatesolution. After having been washed with water, it constitutes a lightyellow powder which is covered by pouring methanol upon it and, onacidifying with meth anolic hydrochloric acid, it is transformed, withevolution of carbon dioxide, into the yellow dihydrochloride of the basenamed above. When recrystallised from methanol and acetone, it melts at230 C. with decomposition.

The starting material is obtained in a manner analogous to thatdescribed in Example 3 by using, instead of methyl, theallyl-acetoacetic acid which is formed in a manner analogous to theprocess described in Example 1, by shaking the ester for several dayswith caustic potash solution. A feebly reddish, fine crystalline powderis formed. The base may be precipitated from the aqueous solution bymeans of dilute caustic soda solution. After recrystallisation fromwater and a small quantity of meth anol, the base is substantiallycolorless; on drying it assumes a brownish-yellow coloration; it meltsunsharply at about C. Bymeans of sodium carbonate a carbonate isprecipitated which crystallises from water in the form of small brownneedles melting at 66-67 C.

38 grams of pyroracemic aldehyde-paraguanidinophenylhydrazonehydrochloride in'100 cc. of water are heated on the water-bath togetherwith a solution of 25 grams of aminoguanidine carbonate in about cc. of2 N-hydrochloric acid. After the addition of hydrochloric acid in excessand cooling in ice, the dihydrochloride of the above compound isfiltered with suction and Washed with'2 N-hydrochloric acid and acetone.It is purified by dissolving it in water, filtering the solution andreprecipitating with hydrochloric acid in excess. A substantiallycolorless powder is obtained after recrystallisation from methanol and asmall quantity of water with subsequent addition of acetone. The powdermelts at 275 C.276 C. with decomposition. i

The starting material is obtained 'by the process described in Example1, using para-aminophenyl-guanidine instead of para-amino-benzamidine. Aweak reddish, crystalline powder is formed which, afterrecrystallisation from water, melts at 278 C. with decomposition.Paraamino-phenyl-guanidine may be obtained in the form of the carbonatewhen recrystallised from water, melting at 180-181 C. withdecomposition) by precipitating with saturated potash solution in excesseither the catalytically reduced nitro-compound or thepara-acetamino-phenylguanidine (obtained from para-amino-acetanilide andcyanamide, the carbonate when recrystallised from water melting at 220C. with decomposition) saponified with dilute hydrochloric acid.

Example8 14 grams of pyroracemic aldehyde-para-(guanyl hydrazone ormyl)-phenyl-hydrazone hydrochloride are heated on the water-bath togetherwith 70 cc. of water and a solution of 7.5 grams of aminoguanidinecarbonate in about 35 cc. of 2 N-hydrochloric acid until dissolution iscomplete, whereupon the solution is mixed with hydrochloric acid inexcess and the dihydrochloride of the compound of the formula givenabove is well cooled, filtered with suction and washed with ice-colddilute hydrochloric acid and acetone. It constitutes a red-brown powderwhich readily dissolves in water and forms a red solution. The powder isrecrystallised from methanol and acetone; it then constitutes a browncrystalline powder melting at 266 C. with decomposition. The nitratewhem recrystallised from water melts at 250": -251 C. with decompositionThe starting. material mayvbe prepared in the mannerdescribed=in-Example 1 from paraamino benzalguanyl-hydrazeneandacetoacetic acid; and when resrystallised from waterit iconstitutes-a brown-red'powdermelting.;,at 120 C with. decomposition.- Thepara-'ammo-benzalguanyl-hydrazone maynbe obtained as-carbonate in theform of a yellow powder by precipitating with potassium carbonatesolution para-acetamino-benzalguanyl hydrazone (when recrystallized fromwater, melting-at-238 C. with decomposition) which has been saponifledwith dilute hydrochloric acid. The powder thus obtained melts at 235 C.with decomposition.

18 grams ofpyroracemic aldehyde-meta-(gua nyl hydrazone formyl)-phenyl-hydrazone' by drochloride' are heated on the water-bath, whilesth'ring -together with 8O cc.-- of water and a foobly acid solution of10 grams of amino-guanidine carbonate in-about 50 cc. of 2N-hydrochloric acid; A -dark-redsolution .is obtained within about /1hour. On additionof hydrochloric acid in excesspa light-brown magma ofthe dihydrm chloride -of'the above'base is formed which is cooled inice, filtered with suction and washed withdilute hydrochloric acid andacetone. A reddish-grey powder is obtained'which on dissolving -in waterforms a red solution. It may he arecrystallisedifrom alcohol and acetoneand melts. at 149-C.-150 C. with slow decomposition accompaniedbyswelling:

The starting .material =may be prepared as described inExample 8, usingmeta-aminobenzalguanyl-hydrazone (obtained from the nitrocompound bycatalytic-reduction; the dihydro chloride -melts at"2'75 C.. withdecomposition). When recrystallised from water,it constitutes a teeblybrownish powder which 'assumesa blackviolet. coloration by the additionof concentrated hydrochloric acid; The powder melts-at 222: C.

withrdecompositiomi.

Example 10 ([JH: OH; NH NH.N=c- :=N.NH.c

NH: 0 HiN A diazonium hydrochloride solution of paraarnino benzamidineis reduced at a temperature between -10 'C'. and 5 C. with a strongstanno'uschloride solution inhydrochloric acid, the reduction product isneutralised with caustic soda solution, the solution is detinned andevaporated to-dryness under reducedpressurefithe residue is extractedwith alcohol and the alcoholic ex tractis mixed with'ether. Thedihydroc'hloride of; the'para hydrazine-benzamidine .is thus :obtainedwhich is recrystallised from alcohol and then melts at 211 C.2l2 C. withdecomposition. A solution of- 3 grams of this salt 'ismixed with a hotaqueous solution'of. 1.75 grams of diacetylmonoguanyl-hydrazoneand-the-mixture' is acidifled-awith dilute hydrochloric acid; After sometime dilute'hydrochloric acid is added in excess,

after cooling in ice the-precipitate is-filtered with suctionand. washedwithice-cold dilute hydrochloric'acid and acetone. The pale yellowpowderis soluble in water. andforms a yellow solution. The nearly colorlessbase, the* diacetyl- (guanyl) (para-guanyl-phenyl) bis hydrazone, isprecipitated from the solution by means of dilute caustic soda solution.The-base melts at 240-241 C; with decomposition-L The mixture with thebase of Example 3 has the same'm'elting point.

The diacetyl monoguanyl hyd'razon'e (when recrystallisedfrom water,melting at 214 C. with violent decomposition) may'be 'obtainedbyf'ca'refill reaction 'of (11061; 1 with the hydrochloride of"amino-guanidine.

Example-.11

Pyror acemic aldehyde-para-tormyl-phenyl-hy drazon'e may be obtained 1by-- coupling diaz'oti'rled paraami'no-benzaldehyde with acetoac'etic'acid. Wheni'ecrystallised from benzene, the compound constitutes-afeebly reddish po'Wdrmelting'ht 152- 3 grams of thehydrazonethusobtained are dissolved in l methanol, the solution is mixedwith a hot aqueous solution -of "45'gr'ams=ot amino-guanidine nitratefand, after the "addition of asmall quantityot dilute nitric acidi'themix ture is -hea'tedfor a prolonged'tinieon' the waterbath. After theadditionof dilute'nitric acid in excess, the dinltr'ate of theua'hyl-hydrdzohopyroracemic aldehyde (para=guanyl-hydrazono formyl)-phenyl-hydrazone is filtered with suction and washed-withwateri whenrecrystallised front-water, the product melts at 250 01-251- C. withdecomposition.- The mixtur'e"wit-h the 'dinitrate ot EiiampleB has'thesame melting point.

Example 12 v CH3 NH'.N=cH. =N.Nn.o

(LEN

HrN

10.15 grams of pyroracemicaldehyde-metaguanidino-phenylhydrazone-nitrate are heated for 1 hour ina water-bath together witha solution of :5 gramsofaminog-uanidine-nitrate in 005 of-water'having 'been'aoidifled withdilute-hy drochloric acidx The-solution produced-separates on coolingthe dinitrate-oi the above-named base which is filtered -withsuction-and then washed first with water and then with acetone. It may-.be* recrystallized from aqueous methanol, with a subsequent additionofacetone, and'then forms'- a--fine, crystal-line, reddish-gray powderwhich'sparingly dissclves in cold water,- but readily-' dissolves in hotwater. The product melts at 284 0., .withdeoomposition; The basedissolves in sodium hydroxide solution used in excess.

The starting-;material may 'beprepared as follows 12 grams ofmeta-acetaminophenylguanidine-carbonateiobtained from the hydrochloride-0f=meta-amino -acetanilideand cyanamide byprecipitation -with'potassiumcarbonate solution;afterthe recrystallization from water,the-nitrate-melts "at 205 C., with decomposition) are-heated for- 1hourin awater-bath together With- BO -cc.--ofwater and'20- cc. ofconcentrated hydrochloricacid. Thehydrochlorideofmetaaminop'henyl-guanidine which is formed during this heatingoperation is diazotized with 3.5 grams of sodium nitrite and thediazonium solution is mixed with an acetoacetic acid solution obtainedby saponification of 7.5 grams of acetoacetic ester with 3.5 grams ofcaustic potash in 125 cc. of Water and a subsequent acidification with60 cc. of Z-n-hydrochloric acid. After the addition of saturated sodiumacetate solution to the mixture until a reaction to mineral acid can nolonger be detected, a red coloration sets in with evolution of carbondioxide and, after the addition of dilute nitric acid in excess, thepyroracemic aldehyde-meta-guanidino -phenyl-hydrazone nitrate separatesand is filtered with suction and then washed with very dilute nitricacid and acetone. After the recrystallisation from methanol and acetone,the product melts at 218 C. with decom position. It constitutes a feeblyreddish, crystalline powder.

Example 13 EN OH; OH; NH

\ &

C.HN NH.N=O- =N.NH.C HEN NH:

'7 grams of diacetyl-para-guanidino-phenylhydrazone-hydrochloride areheated, while stirring, for 1-2 hours in a water-bath together with 3.6grams of aminoguanidine-nitrate in about 150 cc. of water, after theaddition of a small quantity of dilute hydrochloric acid. Dilute nitricacid in excess is then added and after cool ing the product is filteredwith suction and washed with very dilute nitric acid and with acetone.The dinitrate of the above base is thus obtained in the form of a paleyellow powder which rather readily dissolves in hot Water to form ayellow solution, but which is hardly soluble in cold water. On stirringwith hot sodium hydroxide solution, the base is formed which, whenrecrystallized, still in the moist state, from methanol, constitutes,after drying, a goldenyellow powder. The product melts at 180 C. withdecomposition. It is readily soluble in dilute acetic acid; with dilutehydrochloric acid in excess it forms the crystalline, colorlessdi-hydrochloride.

The starting material is obtained by the addition of saturated sodiumacetate solution to the mixture of a diazonium hydrochloride solution ofpara-aminophenylguanidine with a methyl-acetoacetic acid solution in theform of a solid, colorless hydrochloride. When recrystallized fromaqueous methanol with the subsequent addition of acetone, the productmelts at 300 C. with decomposition.

Example 14 011, OH: NH

NH.N. =N.NH.C

16 grams of di-acetyl-meta-(guanylhydrazoneformyl)-phenylhydrazone-hydrochloride and 7.5 grams of aminoguanidine-nitrateare heated in the water-bath in '75 cc. of water which has beenacidified with dilute hydrochloric acid, during which operation a verydark-red solution is gradually formed. While the solution is still hot,it is mixed with dilute nitric acid in excess.

After cooling, the dinitrate of the above-named base which has separatedis filtered with suction and washed with n/ l-nitric acid and acetone.It constitutes a reddish-gray powder which readily dissolves in hotwater to form a red solution. When cooled, the solution assumes ajellylike consistency. On heating with dilute sodium hydroxide solution,the base is formed. After recrystallization from methanol and water, afeebly reddish powder is obtained which melts at 238 C. withdecomposition. The powder readily dissolves in dilute acetic acid toform a reddish solution; a jelly-like hydrochloride is precipitated fromthe solution by means of hydrochloric acid applied in excess.

The starting material is obtained in the form of the hydrochloride, asit is described in Example 9, while using methyl-acetaoacetic acid as afeebly reddish powder, which, when recrystallized from methanol andether, melts at 242 C. to 243 C. with decomposition.

This application is a continuation-in-part of application Serial No.237,061 filed July 16, 1951.

I claim:

1. The compounds of the following general formula C.HN

wherein R stands for a member selected from the group consisting ofhydrogen and aliphatic hydrocarbon radicals containing 1 to 3 carbonatoms.

2. The compounds of the general formula (EH3 /NH RN NH.N=CH.C=N.NH.C/

0.1m NH, HaN

3. The compounds of the general formula CH3 CH3 NE g NH.N=C--C=N.NH.O

/CHN EN 4. The compound of the formula OH: NH l NH.N=CH. =N.NH.O N. oJINHIN 5. The compound of the formula HN CH3 NH l /C.HN NH.N=CH.C=N.NH.CHzN NH,

6. The compound of the formula HN on; OH: NH 6 1 (LEN NH.N= o=N.NH.c HzNH:

HEINRICH J ENSCH.

No references cited.

1. THE COMPOUND OF THE FOLLOWING GENERAL FORMULA